Boron compounds

ABSTRACT

PCT No. PCT/GB96/03115 Sec. 371 Date Aug. 26, 1998 Sec. 102(e) Date Aug. 26, 1998 PCT Filed Dec. 17, 1996 PCT Pub. No. WO97/23487 PCT Pub. Date Jul. 3, 1997Process for the preparation of undecahydrododecaborate anions [B12H(12-n)(XCN)n]2- or [B12H11XH]2- or a nonahydrodecaborate anions [B10H(12-n)(XCN)n]2- or [B10H9XH]2- or anions of formula [B12H11SC(NR1R2)2]-1 wherein X=O, S, or Se.

This application is a 371 of PCT/GB96/03115, filed Dec. 17, 1996 nowWO97/23487.

FIELD OF THE INVENTION

The present invention relates to the preparation of boron compounds andin particular the production of substituted undecahydrododecaborateanions [B₁₂ H₁₁ XH]²⁻ and [B₁₂ H.sub.(12-n) (XCN)_(n) ]²⁻, andnonahydrodecaborate anions [B₁₀ H₉ XH]²⁻ and [B₁₀ H.sub.(10-n) (XCN)_(n)]²⁻ where X and n are defined herein.

BACKGROUND

Boron compounds have been used for the treatment of cancer through ¹⁰ Bneutron capture therapy (BNCT). Various derivatives ofdodecahydrodecaborate [B₁₂ H₁₂ ]²⁻ and decahydrodecaborate [B₁₀ H₁₀ ]²⁻have been synthesised. The sulphydryl-containing borane anion [B₁₂ H₁₁SH]²⁻ (BSH) has been found to be a most suitable species for thetreatment of glioma by BNCT. It is found that BSH is preferentiallytaken up by the brain cancer tumour (glioma), which allows selectivetargeting of thermal or epithermal neutrons. Presently, there is notreatment for glioma and early death of the patient is to be expected.

The compound BSH has been known for some time and is approved fortherapy in the USA. A number of syntheses of BSH have been reported inthe literature (W. H. Knoth, J. C. Sauer, D. C. England, W. R. Hertlerand E. L. Muetterties, J. Am. Chem. Soc., 1964, 86, 3973; E. I. Tolpin,G. R. Wellum and S. A. Berly, Inorg. Chem., 1978, 17, 2867; T. Nakagawa,T. Yoshizaki and K. Aono, J. P. Kokai 75 92897 C.A. 1976 84: 79701v; M.Komura, K. Aono, K. Nagasawa and S. Sumimoto, Chem. Express, 1987, 2,173; V. A. Brattsev and O. R. Sagitullin Pat. USSR 1328290 (1987) C.A.;1987, 107: 179481k). However, these synthetic methods are complicatedand generally involve many synthetic steps. Certain of the intermediateproducts may be toxic, which leads to purification problems. Finally,the overall yields are generally poor. All syntheses start from thedodecahydrododecaborate anion [B₁₂ H₁₂ ]²⁻ which can be obtained in highyield when decaborane is treated with triethylamine-borane (N. N.Greenwood and J. H. Morris, Proc. Chem. Soc., 1963, 338.) B₁₀ H₁₄ +2Et₃NBH₃ →[Et₃ NH]₂ [B₁₂ H₁₂ ]+3H₂.

Alternatively, it can be obtained by the reaction: 10BH₃ SMe₂ +2NaBH₄→Na₂ [B₁₂ H₁₂ ]+10SMe₂ +13H₂ (H. C. Miller, N. E. Miller and E. L.Muetterties, Inorg. Chem., 1964, 3, 1456; W. V. Hough, C. R. Guibert,and G. T. Hefferan, U.S. Pat. No. 3,961,017. C.A. 1976, 85, P126732V).

In the best reported synthesis (Komura et al., see above) seven stepsare involved in converting this compound to Na₂ [B₁₂ H₁₁ SH]. Theoverall yield is 68% though in practice this may represent a maximumrather than a routine achievable yield.

The syntheses of the [B₁₂ H₁₁ SCN]²⁻ anion, as salts with the cations[Et₃ NH]⁺, [Et₄ N]⁺, [(Ph₃ P)₂ N]⁺, Na⁺, or Cs⁺, are more efficient thanearlier reported preparations (e.g. H. -G. Srebny and W. Preetz, Z.anorg. allg. Chem., 1984, 513, 7). Previously reported methods requirethe inconvenient prior preparation of (SCN)₂ from Pb(SCN)₂ and Br₂, andthe use of [Bu₄ N]₂ [B₁₂ H₁₂ ] in CH₂ Cl₂. The methods of the presentinvention conveniently start from simple thiocyanate salts, and easilysynthesised salts of [B₁₂ H₁₂ ]²⁻ with the cations [Et₃ NH]⁺, Na⁺, orK⁺. The reactions may also be carried out in aqueous solutions andprovide quantitative yields. The compound, as its sodium salt, hasexcellent potential for neutron capture therapy, in view of its lowbiological toxicity, and good tumour-localising properties in a tumourmodel system.

The synthesis of the 1,7-isomer (and the 1,12-isomer as a smallbyproduct) of salts of [B₁₂ H₁₁ (SCN)₂ ]²⁻ have not been reportedpreviously. Such compounds are also believed to have potential forneutron capture therapy.

SUMMARY OF THE INVENTION

It is an object of the present invention to mitigate these problems andprovide a simpler process capable of good yield.

It is a further object to develop new compounds for neutron capturetherapy.

These and other objects of the present invention will become apparentfrom the following description.

The present invention provides a process for the preparation ofundecahydrododecaborate anions [B₁₂ H.sub.(12-n) (XCN)_(n) ]²⁻ or [B₁₂H₁₁ XH]²⁻ or nonahydrodecaborate anions formula [B₁₀ H.sub.(10-n)(XCN)_(n) ]²⁻ or [B₁₀ H₉ XH]²⁻ where X=O, S or Se; and n=1, 2 or 3;which comprises the reaction of a dodecahydrododecaborate anion [B₁₂ H₁₂]²⁻ or decahydro decaborate anion [B₁₀ H₁₀ ]²⁻ with a compound A⁺ NCX⁻

where A⁺ =an alkali metal cation selected from Li, Na, K or Cs;

an alkaline earth metal cation selected from 1/2Ca, 1/2Mg;

[R₄ P]⁺, [R₃ HP]⁺, [R₄ N]⁺, [R₃ HN]⁺ ;

where R is a C₁₋₂₀ alkyl, aryl, or C₁₋₂₀ alkyl substituted aryl group;

the reaction being either an electrochemical oxidation reaction, or thereaction being conducted in the presence of an oxidising agent.

In order to ensure complete reaction, the amount of electrical chargesupplied in the electrochemical or chemical oxidation will generally besufficient to bring about the one-electron oxidation of the NCX ion togenerate the radical NCX. Without wishing to be limited by anyspeculated mechanism, it is believed that this radical subsequentlyreacts with [B₁₂ H₁₂ ]²⁻ as follows:

    [B.sub.12 H.sub.12 ].sup.2- +2[NCX]→[B.sub.12 H.sub.11 XCN].sup.2- +HXCN

so that in general the reaction may be viewed as representing a twoelectron process. In the case of chemical oxidation, the oxidant may behydrogen peroxide, benzoyl peroxide, cupric ion, ceric ion, chromate ordichromate ion, or halogen e.g. Cl, Br, F, or I. The oxidant ispreferably used in acid solution.

Generally, the [B₁₂ H₁₂ ]² - anion used as starting material will be inthe form of the compound [Et₃ NH]₂ [B₁₂ H₁₂ ]. However, other analogousstarting materials may also be used, including [R₄ N]₂ [B₁₂ H₁₂ ] (whereR is preferably methyl, ethyl, propyl or butyl) or (W)₂ [B₁₂ H₁₂ ]wherein W represents Cs, K, Na or Li.

The reaction set out above generally gives rise to the compound A₂ [B₁₂H₁₁ XCN]²⁻ or A₂ [B₁₀ H₉ XCN]²⁻ respectively. Further reaction withadditional [NCX]. produces multiple substituted anions for example, [B₁₂H₁₀ (XCN)₂ ]²⁻ or [B₁₀ H₈ (XCN)₂ ]²⁻. These intermediates may then bereduced for example using sodium in liquid NH₃ to give the correspondingsalts for example A₂ [B₁₂ H₁₁ XH] or A₂ [B₁₀ H₉ XH].

In order that the intermediate compounds are more easily separated fromthe reaction mixture, it is preferred that the cation A shall be a bulkycation, such as the ammonium and phosphonium cations mentioned above.Preferably, R is a C₁₋₈ alkyl group. Preferred aryl groups includephenyl, tolyl and naphthyl groups.

The electrochemical reaction is usually carried out in the solutionphase employing a solvent of high conductivity and high dielectricconstant. So as not to be decomposed during the electrochemicalreaction, the solvent must have a good oxidation/reduction range.Ideally, the solvent should be volatile enough for easy removal undervacuum. Preferred solvents include acetonitrile, dimethylsulphoxide,dimethylformamide, nitromethane, and water.

In a further aspect of the invention there is provided a process for thepreparation of an undecahydrododecaborate anion of the formula

    [B.sub.12 H.sub.11 XH].sup.2-

wherein X is S or Se;

which comprises

(i) the reaction of a dodecahydrododecaborate anion [B₁₂ H₁₂ ]²⁻ with acompound X=C(NR¹ R²)₂ wherein R₁ and R² are the same or different andare selected from H and C₁ -C₆ alkyl; the reaction being either anelectrochemical oxidation reaction or the reaction being conducted inthe presence of an oxidising agent and resulting in the formation of aurea derivative of the formula

    [B.sub.12 H.sub.11 XC(NR.sup.1 R.sup.2).sub.2 ].sup.- ; and

(ii) the hydrolysis of said urea derivative under alkaline conditions.

In a preferment, the urea derivative is a thiourea derivative wherein Xis S and R¹ and R² are both H.

The preparation of [B₁₂ H₁₁ XH]²⁻, when produced by way ofelectrochemical oxidation is typically carried out in an electrochemicalcell with anode and cathode compartments being separated by asemi-permeable anion exchange membrane. Generally, a suitable supportingelectrolyte, such as CF₃ SO₃ NBu₄ in acetonitrile, is required. In stage1 of the process, in the presence of a suitable supporting electrolytethe following reaction takes place:

    [B.sub.12 H.sub.12 ].sup.2- +X=C(NR.sup.1 R.sup.2).sub.2 →[B.sub.12 H.sub.11 XC(NR.sup.1 R.sup.2).sub.2 ].sup.- +H.sup.+

The reaction product may be transferred into an acid such as H₃ O⁺ [B₁₂H₁₁ XC(NR¹ R²)₂ ]⁻ by passing the reaction mixture through a column madeup of a suitable resin, such as Dowex 50 resin in H-form and purified byrecrystallisation of an alkali metal salt of the anion, for example, thecesium salt from water and ethanol mix, in a suitable ratio, for examplea ratio of 3 parts ethanol: 1 part water.

The alkali metal salt of the [B₁₂ H₁₁ XC(NR¹ R²)₂ ]⁻ anion is thensubjected to hydrolysis under suitable alkaline conditions, e.g. 1M NaOHfor 10 minutes at up to 80° C. or may be subjected to reflux conditions,for example for about 1 hour in 10% NH₄ OH: [B₁₂ H₁₁ XC(NR¹ R²)₂ ]⁻ +OH⁻(NH₃)→[B₁₂ H₁₁ XH]²⁻ +(R² R¹ N)₂ CO[(H₂ N)₃ C]⁺

In a further aspect of the present invention, intermediate cations areprovided which are formed during the electrochemical oxidation reactionor the reaction conducted in the presence of an oxidising agent, of thefollowing formula:

    [{(R.sup.1 R.sup.2 N).sub.2 CX}.sub.2 ].sup.2+

wherein R¹ and R² are the same or different and are selected from H andC₁ -C₆ alkyl; and X is S or Se.

The reaction with NH₃ may be used as a basis for the preparation ofsubstantially pure BSH. For example, after ammonolysis, the reactionmixture can be evaporated to dryness and the residue, comprised ofsuitable cations such as alkali metal ions and the like, for example,Cs⁺ and guanidinium ion can be dissolved in water and passed through asuitable cation exchange column, comprising, for example, a Dowex 50resin in H-form. The eluate can then be neutralised with alkali, forexample, NaOH, to a suitable pH, for example pH 5-6, filtered anddispensed into containers prior to storage. Generally, all of the abovereactions are carried out under non-oxidative conditions such as in anitrogen gas atmosphere or the like.

For reasons of convenience, it is preferred if X is S and R¹ and R² areboth H.

The selenium compounds and thiourea derivatives of the present inventionare novel. Therefore, another aspect of the present invention providesnovel anions of the formulae [B₁₂ H₁₁ (SCN)₂ ]²⁻, [B₁₀ H₉ SeH]²⁻, [B₁₂H₁₁ SeH]²⁻, [B₁₀ H₉ SeCN]²⁻, [B₁₂ H₁₁ SeCN]²⁻, [B₁₂ H₁₀ (SeCN)₂ ]²⁻,[B₁₂ H₁₁ SC(NR¹ R²)₂ ]⁻ and [B₁₂ H₁₁ SeC(NR¹ R²)₂ ]⁻ wherein R¹ and R²are the same or different and are selected from C₁ -C₆ alkyl and H.

A further aspect of the invention provides sulphur and seleniumcompounds together with a pharmaceutical carrier for use in medicaltherapy, particularly BNCT. Thus, there is provided use of a sulphur orselenium containing compound selected from [B₁₀ H₉ SeH]²⁻, [B₁₂ H₁₁SeH]²⁻, [B₁₀ H₉ SeCN]²⁻, [B₁₂ H₁₁ SeCN]²⁻, [B₁₀ H₉ SCN]²⁻, [B₁₂ H₁₁SCN]²⁻, [B₁₂ H₁₀ (SCN)₂ ]²⁻, [B₁₂ H₁₁ SC(NR¹ R²)₂ ]⁻ and [B₁₂ H₁₁SeC(NR¹ R²)₂ ]⁻ wherein R¹ and R² are the same or different and areselected from C₁ -C₆ alkyl and H together with a pharmaceutical carrierin the manufacture of a medicament for the treatment of cancer.

Examples and Figures illustrating the present invention follow. It is tobe understood that the examples are not to be construed as limiting thescope of the invention in any way.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: IR spectrum of Cs [B₁₂ H₁₁ SC(NH₂)₂ ] in nujol.

FIG. 2: ¹¹ B NMR spectra (Rel. Et₂ OBF₃) of (a,b) [B₁₂ H₁₁ SC(NH₂)₂ ]⁻and (c,d) [B₁₂ H₁₁ SH ]²⁻ from its alkaline hydrolysis.

EXAMPLE 1 (X=O)

An electrochemical cell was set up, of two U-shaped compartments, wherethe anodic and cathodic compartments were separated by NAFION ionexchange membrane. The working electrode consisted of platinum gauze,the auxiliary electrode of platinum foil, and the reference electrodewas a silver wire.

An EG and G Princeton Applied Research potentiostat.galvanostat was usedwith a limiting current of 100 mA and a potential of 0.8V. Acetonitrilewas purified by the method used by Winfield and co-workers (J. M.Winfield, J. Fluorine. Chem., 1984, 25, 91).

[C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ] (Boron Biologicals Ltd, U.S.A.) (0.49 g, 2mmol) and [(Ph₃ P)₂ N] [NCO] (Aldrich Chemical) (2.32 g, 4 mmol) inacetonitrile (40 ml) were added to the anodic compartment of the cell.The cathodic compartment contained [(Ph₃ P)₂ N] [NCO] (1.16 g. 2 mmol)as conducting electrolyte for the reaction in acetonitrile solvent (15ml).

After 386 Coulombs (4 mmol) of charge had passed, the reaction wasstopped. At this stage the solution was taken up to dryness to produce agum. The gum was taken up in warm 28% aqueous ethanol and left to coolto produce white crystals of [(Ph₃ P)₂ N]₂ [B₁₂ H₁₁ OCN] (0.617 g, 0.5mmol), 24% yield. The compound was identified by ¹¹ B and ¹ H nmrstudies.

EXAMPLE 2 (X=S) (A) Preparation of [Ph₃ P)₂ N] [SCN]

[(Ph₃ P)₂ N] [Cl] (Aldrich Chemical) (11.47 g, 20 mmol) was dissolved inwarm water and to this was added a solution of [NH₄ ] [NCS] (1.52 g, 20mmol) in as little water as possible. A white precipitate appearedimmediately and the solution was filtered. Recrystallisation was carriedout using CH₂ Cl₂ /Et₂ O solvent to produce [(Ph₃ P)₂ N] [SCN] (10.73 g,18 mmol).

The infra-red spectrum indicates the NCS stretching mode at 2,120 cm⁻¹.

Found: C, 47.0; N, 4.67; S, 5.31; H, 5.0%. [(Ph₃ P)₂ N] [NCS] requires:C, 74.50; N, 4.70; S, 5.37; H, 5.03%.

(B) Electrochemical Preparation of [(Ph₃ P)₂ N]₂ [B₁₂ H₁₁ SCN]

[(C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ] (0.49 g, 2 mmol) and [(Ph₃ P)₂ N] [SCN] (2.38g, 4 mmol) in acetonitrile solvent (40 ml) were placed in the anodiccompartment of the cell. The cathodic compartment contained [(Ph₃ P)₂ N][SCN] (1.19 g, 2 mmol) as conducting electrolyte for the reaction inacetonitrile solvent (15 ml).

After 386 Coulombs (4 mmol) of charge had passed, and the solutionbecame more intensely yellow in colour the reaction was stopped. At thisstage the solution was taken to dryness under vacuum to produceyellowish gum. The gum was taken up in warm 20% aqueous ethanol and leftto cool to produce white crystals of [(Ph₃ P)₂ N]₂ [B₁₂ H₁₁ SCN] (1.87g, 1.5 mmol, 73% yield) as indicated by ¹¹ B and ¹ H nmr studies.

EXAMPLE 3 (X=S) (A) Preparation of [C₂ H₅)₃ NH] [SCN]

A solution of [NH₄ ] [SCN] (Aldrich Chemicals) (7.6 g, 0.1 mmol) inacetonitrile (80 cm³) was added to a solution of (C₂ H₅)₃ N (14 cm³, 1mmol) in acetonitrile (40 cm³) and acetic acid (6 cm³, 0.11 mmol).Immediately a white crystalline product precipitated, which was filteredoff, washed several times with acetonitrile, and dried in vacuo to yielda constant weight of 13.5 g. (84%) of pure [(C₂ H₅)₃ NH] [SCN]. Sincethe compound is very hygroscopic, it is stored in a tightly closedvessel.

(B) Electrochemical Preparation of Cs₂ [B₁₂ H₁₁ SCN]

A similar preparation was carried out (as previously) using [(C₂ H₅)₃NH] [SCN] (0.32 g, 2 mmol) in the place of [(Ph₃ P)₂ N] [SCN].

After evaporation to dryness under vacuum, a yellow/orange gum produced.CsOH (0.3 g, 10-20% water content) was dissolved in as little water aspossible and to this was added the yellow gum. Triethylamine vapour wasgiven off to produce white crystals of Cs₂ [B₁₂ H₁₁ SCN] (0.66 g, 1.5mmol, 73% yield) which were filtered and washed with ethanol.

EXAMPLE 4 (X=S) Preparation of TetraethylammoniumS-(thiocyano)-closo-dodecaborate [(C₂ H₅)₄ N]₂ [B₁₂ H₁₁ SCN]

To the suspension of 9.30 g (26.9 mmol) [(C₂ H₅)₃ NH)]₂, [B₁₂ H₁₂ ] in50 ml of water there was added 15 ml (75 mmol) of 5M NaOH and themixture was partially evaporated in vacuo till complete dissolution ofthe precipitate. The resulting solution of Na₂ [B₁₂ H₁₂ ] was adjustedto 50 ml volume with water and cooled with ice water. 30 ml ofconcentrated H₂ SO₄ was added to 30 ml of water under ice cooling and tothe cooled solution there was added 50 ml (100 mmol) of 2M H₂ O₂. Theprepared solution was poured into the solution of Na₂ [B₁₂ H₁₂ ].

Under mechanical stirring and ice cooling 6.3 g (53.6 mmol) of NaSCN.2H₂O in 12 ml of water were added and stirring continued until completedisappearance of the purple colour of the reaction mixture. To the clearsolution of the reaction mixture a solution of 13.00 g (59.9 mmol) [(C₂H₅)₄ N] [BF₄ ] in 30 ml H₂ O was added. A white crystalline precipitatewas formed which was filtered off, washed with water (3×30 ml) andrecrystallised twice from hot water yielding 10.47 g (83.3%) of [(C₂H₅)₄ N]₂ [B₁₂ H₁₁ SCN].

The ¹¹ B NMR spectrum of the prepared compound consists of a singletintensity 1 at -9.7 ppm and 3 doublets at -14.4, -14.9 and -16.8 ppm ofrelative intensities 5:5:1 indicating a monosubstituted closo-B₁₂derivatives.

IR spectrum of the compound measured in nujol H mull contains a sharpband at 2138 cm⁻¹ indicating the presence of a CN group and a broad bandof B--H vibrations at 2600-2800 cm⁻¹.

EXAMPLE 5 (X=S) Electrochemical Thiocyanation of [(C₂ H₅)₃ NH]₂ [B₁₂ H₁₂]

The anode cell of the electrochemical unit was loaded with 1.00 g (2.89mmol) of [(C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ] 0.62 g (8.15 mmol) of NH₄ SCN and40.0 ml of CH₃ CN. Into the cathode cell 0.30 g (3.95 mmol) NH₄ SCN and15.0 ml CH₃ CN were placed. The potential in the anode cell was adjustedto +1.00V and electrolysis started. Evolution of H₂ was observed at thecathode. Under stirring the precipitate of [(C₁₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ]was slowly dissolved and the temperature increased to 38-40° C. Thereaction was continued till the consumption of 600 Coulombs (107.5%,calculated to the mono-substituted product) and then stopped. To thereaction mixture 40 ml of water and 2.0 ml 5M NaOH were added and thesolution was evaporated in vacuo to dryness. The solid residue wasdissolved in 15 ml of water and 1 ml of acetic acid. The solution wasfiltered and precipitated with 5 ml 2M [(C₂ H₅)₄ N] Br. The precipitateformed was filtered off and recrystallised from hot water. After dryingin air 1.04 g (75.5%) of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₁ SCN] were obtained.

IR spectrum of the sample of the prepared compound in nujol showed anintense absorption band of CN stretching vibrations at 2138 cm⁻¹ and abroad band of B--H vibrations at 2600-2800 cm⁻¹.

¹¹ B NMR spectrum of the sample consists of 4 resonance frequencies at-9.7, -14.9 and -16.8 ppm of relative intensities of 1:5:5:1. Theresonance band at -9.7 ppm is a singlet in the ¹¹ B proton nondecoupledspectrum indicating monosubstituted closo-B₁₂ moiety.

EXAMPLE 6 (X=Se) Electrochemical Preparation of Cs₂ [B₁₂ H₁₁ SeCN]

[C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ] (0.49 g, 2 mmol) and KSeCN (0.58 g, 4 mmol) inacetonitrile solvent (40 ml) was placed in the anodic compartment of thecell. The cathodic compartment contained KSeCN (0.29 g, 2 mmol) asconducting electrolyte for the reaction in acetonitrile solvent (15 ml).

After 400 Coulombs (4.1 mmol) of charge had passed, the solution becameintense red in colour, and the reaction was stopped.

The solution was taken to dryness to produce a red gum. CsOH (0.8 g,10-20% water content) was dissolved in as little water as possible andthe red gum was added to this to produce crystals which were filteredand washed with 20% aqueous ethanol to give Cs₂ [B₁₂ H₁₁ SeCN] (0.73 g,1.5 mmol, 72% yield) indicated by ¹¹ B and ¹ B nmr studies.

Resonances were observed at -11.65, -13.95, -15.10, -17.05 ppm ofrelative intensities 1:5:5:1 from the ¹¹ B {¹ H} spectrum.

The ¹¹ B spectrum contains a singlet at -11.65 ppm representing the SeCNcontaining boron atom.

EXAMPLE 7 Preparation of Na₂ [B₁₂ H₁₁ SH]

Reduction of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₁ SCN] (Example 5) with sodium inliquid NH₃ was carried out as follows. To 2.52 g (5.5 mmol) of [(C₂ H₅)₄N]₂ [B₁₂ H₁₁ SCN] placed in a 100 ml round bottomed flask 70 ml of dryliquid ammonia was added and a clear solution was formed. 0.8 g ofsodium metal was added in small pieces to this solution, waiting eachtime for the complete disappearance of the blue colour. Addition ofsodium was continued until the appearance of persistent blue colour. Theammonia was allowed to evaporate and the rest of volatile products wascompletely removed in vacuo. The flask containing a dry solid was filledwith dry nitrogen, and then there were successively added 10 ml ofethanol, 15 ml of glacial acetic acid and 2 ml of thioglycolic acid. Themixture was heated to 80° C. for 5-10 minutes for complete dissolutionof the solid, the hot solution filtered, 30 ml of diethyl ether wasadded and the mixture left for 20-30 minutes at room temperature tocrystallise.

A white precipitate was formed which was filtered off, washed withacetic acid and dried in vacuo, yielding 1.04 g (86%) of Na₂ [B₁₂ H₁₁SH]. After recrystallisation from acetic acid under nitrogen there wasobtained 0.92 g (76%) of Na₂ [B₁₂ H₁₁ SH] which was characterised by its¹¹ B NMR spectrum. The sample of Na₂ [B₁₂ H₁₁ SH] contained as impurity1.7% of Na₂ [B₁₂ H₁₂ ].

EXAMPLE 8 Preparation of Na₂ [B₁₂ H₁₁ SCN] from [(C₂ H₅)₄ N]₂ [B₁₂ H₁₁SCN]

[(C₂ H₅)₄ N]₂ [B₁₂ H₁₁ SCN] (3.30 g, 7.2 mmol) was dissolved in amixture of CH₃ CN (6 cm³), H₂ O (6 cm³), and CH₃ OH (3 cm³) and thesolution was passed through a column filled with 15 cm³ of cationiteDowex 50 in its H⁺ form which had been previously washed with a similarmixture of solvents. An acid fraction was collected and titrated withNaOH to pH 7.0 and required exactly 14.4 mmol for neutralisation. Theclear solution was evaporated to complete dryness on a rotary evaporatoryielding 1.80 g of Na₂ [B₁₂ H₁₁ SCN]. The i.r. spectrum of the compoundshowed a sharp band of 2138 cm⁻¹ due to the C.tbd.N group, and a broadband at 2600-2800 cm⁻¹ due to B--H stretching vibrations.

The compound is very soluble in water, and this enhances its applicationin biological trials in animal models.

EXAMPLE 9 Preparation of Na₂ [B₁₂ H₁₀ (SCN)₂ ] from [(C₂ H₅)₄ N]₂ [B₁₂H₁₀ (SCN)₂ ]

A solution of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₀ (SCN)₂ ] (Example 11) (1.80 g, 3.5mmol) in a mixture of CH₃ CN: H₂ O: CH₃ OH (2:2:1) was passed through acationite Dowex 50 in its H⁺ form, neutralised with NaOH, and evaporatedto dryness to yield 1.1 g of Na₂ [B₁₂ H₁₀ (SCN)₂ ]. The compound, whichwas freely soluble in water, showed a strong sharp i.r. band at 2140cm⁻¹ due to the C.tbd.N groups.

EXAMPLE 10 Electrochemical Thiocyanation of [B₁₂ H₁₂ ]²⁻ in Aqueous AcidSolution

To the anode compartment of the electrochemical cell were placedsequentially 6 cm³ of 0.5M Na₂ [B₁₂ H₁₂ ] (3.0 mmol), 2 cm³ of 5.0MNaSCN (10 mmol), 24 cm³ of water and 8 cm³ of H₂ SO₄ (1:1 v/v). In thecathode compartment were placed 1 cm³ of 5.0 M NaSCN, 11 cm³ of waterand 3 cm³ of H₂ SO₄ (1:1 v/v). The cell was cooled in ice and theelectrochemical process started at a potential of 0.6V (I.sup.˜ 300 mA).After passing 580 Coulombs, the reaction was stopped and the clearsolution was treated with 15 cm³ of 0.5M [(C₂ H₅)₄ N] [BF₄ ] (7.5 mmol).The white precipitate was filtered off, washed with water, and dried inair yielding 1.25 g (90.7%) of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₁ SCN] ofapproximately 95% purity (by ¹¹ B NMR integral measurements).

EXAMPLE 11 Preparation of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₀ (SCN)₂ ] using K₂ Cr₂O₇ as an oxidizer

To a solution of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₂ ] (9.47 g, 23.55 mmol) {[(C₂H₅)₄ N]₂ [B₁₂ H₁₂ ] can be prepared from a soluble salt such as Na₂ [B₁₂H₁₂ ] or [(C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ] by metathesis with [(C₂ H₅)₄ N]OH or[(C₂ H₅)₄ N]Cl or [(C₂ H₅)₄ N]BF₄ in a molar ratio 1:2 in aqueoussolution by a method similar to that of Example 4}.

To a suspension of [(C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ] (9.3 g, 26.9 mmol) in 50cm³ of water added 15 cm³ of 5M NaOH and the mixture partiallyevaporated in vacuo until complete dissolution had occurred. To thisclear solution, adjusted to 50 cm³ with water and cooled in ice, wasadded a solution of [(C₂ H₅)₄ N]BF₄ (13.0 g, 59.9 mmol) in 30 cm³ water,and the white precipitate filtered off, washed with water, andrecrystallised from hot water. To a solution of [(C₂ H₅)₄ N]₂ [B₁₂ H₁₂ ](9.47 g, 23.55 mmol) in a mixture of 200 cm³ of acetonitrile, 50 cm³ ofwater, and 40 cm³ of H₂ SO₄ (1:1 v/v) cooled to 5-7° C. was added asolution of NaSCN.2H₂ O (12.8 g, 109 mmol) in 20 cm³ of water. Asolution of K₂ Cr₂ O₇ (4.85 g, 16.5 mmol) in 30 cm³ of water and 30 cm³of H₂ SO₄ (1:1 v/v) was added dropwise with stirring giving a slightevolution of heat (temp.=12° C.). The reaction mixture was stirred for0.5 hours and concentrated on a rotary evaporator to strip the CH₃ CN.The residue was refluxed with 1000 cm³ of water and the dark solutionfiltered. On cooling the product separated first as an oil whichsolidified into a crystalline mass on standing. The crystallineprecipitate was filtered off, washed with water, and dried in air,yielding crude [(C₂ H₅)₄ N]₂ [B₁₂ H₁₀ (SCN)₂ ] (10.2 g, 83%). Theproduct was recrystallised from a mixture of 100 cm³ of MeOH and 200 cm³of water. The ¹¹ B NMR spectrum showed it to be almost pure 1,7-isomerof [(C₂ H₅)₄ N]₂ [B₁₂ H₁₀ (SCN)₂ ]. The IR spectrum displayed twointense absorption bands, at 2140 cm⁻¹ (due to C═N str.) and at2600-2800 cm⁻¹ (due to B--H str.).

EXAMPLE 12 Electrochemical Synthesis of [B₁₂ H₁₁ SC(NH₂)₂ ]⁻ Salts

1.012 g (2.92 mmol) of [(C₂ H₅)₃ NH)]₂ B₁₂ H₁₂, 0.520 g (6.84 mmol) ofthiourea and 0.812 g (2.07 mmol) of [Bu₄ N] [O₃ SCF₃ ] (AldrichChemical) were placed into the anode compartment of an electrochemicalcell and dissolved in 50 ml of CH₃ CN. 0.408 g (1.02 mmol) of [Bu₄ N][O₃ SCF₃ ] were placed into the cathode compartment of the cell,dissolved in 15 ml of CH₃ CN, and the reaction started at E=+2.2 V(I=-18 mA) and during the reaction the potential was increased to E=+2.5V (I=-120 mA). The reaction was carried out until gaining 580 coulombs(103%), and then the current switched off. The slightly yellow solutionfrom the anode compartment was diluted with 50 ml of water and passedthrough a column, containing 15 g of a cationite Dowex 50 in H-form inCH₃ CN: H₂ O 1:1. The acidic fraction was collected, neutralized with 5MNaOH to pH 7.5 and the solvent evaporated to dryness in vacuo. The solidresidue was dissolved in 10 ml of water, the solution filtered andtreated with 0.56 g (1.70 mmol) of Cs₂ CO₃. A white crystalline productwas filtered off, washed with water and dried in air, yielding 655 mg(64.3%) of Cs[B₁₂ H₁₁ SC(NH₂)₂ ], which was recrystallised twice fromwater.

By precipitating the diluted aqueous solutions of the cesium salt withEt₄ NBr and Bu₄ NBr respectively the corresponding tetraalkylammoniumsalts were prepared. For Et₄ N[B₁₂ H₁₁ SC(NH₂)₂ ] found: C 31.00, 30.80;H 10.57, 10.41; B 37.03, 36.87; N 12.70, 12.72; S 8.29, 8.32; C₉ H₃₅ B₁₂N₃ S calc: C 31.14; H 10.16; B 37.37; N 12.10; S 9.23. For Bu₄ N[B₁₂ H₁₁SC(NH₂)₂ ] found: C 45.24, 45.24; H 11.61, 11.42; B 27.89, 28.16; N9.13, 9.30; S 5.49, 5.65. C₁₇ H₅₁ B₁₂ N₃ S calc: C 44.45; H 11.19; B28.23; N 9.15; S 6.98.

IR, ¹ H and ¹¹ B NMR spectra of the prepared salts showed unequivocallythat the new derivative of [B₁₂ H₁₂ ]²⁻ represents monosubstitutedthiourea derivative [B₁₂ H₁₁ SC(NH₂)₂ ]⁻ (FIGS. 1 and 2).

EXAMPLE 13 Chemical Preparation of Cs[B₁₂ H₁₁ SC(NH₂)₂ ]

To a solution of 11.0 g (50 mmol) of K₂ B₁₂ H₁₂ (prepared from [(C₂ H₅)₃NH]₂ B₁₂ H₁₂ by treating with KOH) and by 8.0 g (105 mmol) of thioureain 150 ml of 5% H₂ SO₄ a solution of 5.9 g (20 mmol) of K₂ Cr₂ O₇ in 100ml of 5% H₂ SO₄ was added dropwise at room temperature under mechanicalstirring. The reaction mixture was stirred for 1 hour. A solution of14.0 g (85 mmol) of CsCl in 30 ml water was then added to the reactionmixture and the suspension formed was cooled down to 2-4° C. Acrystalline precipitate of Cs[B₁₂ H₁₁ SC(NH₂)₂ ] was filtered off,washed twice in 10 ml aliquots of iced water and re-crystallised twicefrom ethanol-water (3 parts ethanol: 1 part water). The product was thendried in air. IR spectra for Cs[B₁₂ H₁₁ SC(NH₂)₂ ] is shown in FIG. 1.

EXAMPLE 14 Preparation of Cs₂ [B₁₂ H₁₁ SH]

To the solution of 0.70 g (2.00 mmol) of Cs[B₁₂ H₁₁ SC(NH₂)₂ ] in 10 mlof hot water 2 ml (10 mmol) of 5 M NaOH were added together with 20 mgof NaBH₄ (to prevent SH oxidation). The solution was heated to 90° C.and kept at this temperature for 15 minutes. To the hot solution, 0.46 g(1.4 mmol) of Cs₂ CO₃ and 0.2 ml of acetic acid were added and thesolution was cooled with ice water. The crystalline precipitate of Cs₂[B₁₂ H₁₁ SH] formed was filtered off, washed with the deoxygenated waterand dried in vacuo. According to ¹¹ B NMR spectrum the sample containedabout 5% of the disulfide, [Cs₂ B₁₂ H₁₁ S]₂ (FIG. 2).

EXAMPLE 15 Preparation of Na₂ [B₁₂ H₁₁ SH]

A solution of 0.5 g (1.14 mmol) of Cs₂ [B₁₂ H₁₁ SH] in 5.0 ml of hotdeoxygenated water was passed through a column containing 4 g of acation exchange resin, Dowex 50 in H-form. The acidic solution wascollected and neutralised with 5M NaOH. A solution of Na₂ [B₁₂ H₁₁ SH]was obtained.

EXAMPLE 16 Biological Studies on Na₂ [B₁₂ H₁₁ (SCN)]

1. Toxicity Method

The toxicity of Na₂ [B₁₂ H₁₁ (SCN)] was studied in C57BL/6 male mice(Russican Cancer Research Centre, Moscow) of 19-22 grams in weight: Anaqueous solution was injected intraperitoneally in a volume equivalentto 1/100 of each animal's body weight. LD₅₀, LD₁₀₀ and LD₀ were obtainedfor 5 groups (6 mice per group), by the method of Karber (in: M LBelenky "The elements of quantitive estimation of pharmacologicaleffect", Ed. Med. Lit., L-d, 1963, p. 49. (Rus.)). The following doseswere used:

270.0 236.25 202.5 135.0 67.5 μg. boron per gram. of body weight.

2. Toxicity Results

There were no visible behaviour violations observed in the animals afterintraperitoneal injection with the compound. Death at lethal doses didnot occur in less than one day. Surviving animals did not show symptomsof chronic intoxication. The values for Na₂ [B₁₂ H₁₁ (SCN)] were:LD₁₀₀ >270.0; LD₅₀, 236.25; LD₀, 135.0 μg.g⁻¹.

3. Biodistribution Method

The biodistribution of Na₂ [B₁₂ H₁₁ (SCN)] was studied in C57BL/6 mice(20-23 g) bearing the s.c. B-16 melanoma (Russian Cancer ResearchCentre, Moscow). The compound was dissolved in distilled water and thesolution (0.2-0.23 cm³ containing 150 μg. B per g. body weight) wasinjected interperitoneally into C57BL/6 male mice (20-23 g) 11 daysafter the hosts were subcutaneously inoculated with B-16 melanoma cells.The animals were decapitated 1, 3, 6, and 24 hours after injection.Since the successful treatment of neoplasms by the BNCT method requiresa boron concentration gradient between the tumour and the tissueadjacent to it in the radiated volume (B in tumour/B in adjacenttissue>>1) after sufficient clearance of the blood. Therefore, thetumour and the tissues adjacent to it (skin, tumour bed, muscle) wereexcised and the boron content determined. In addition, the blood, urine,tissues of excretory organs (liver, kidneys, lung) and the heart andspleen were analysed. The organs were excised, rinsed in pharmacologicalsaline, dried with filter paper, and weighed. They were then dried toconstant weight. The boron content was determined by prompt gamma rayactivation analysis in the IR-68 reactor at the RRC Kurchatov Institute.The boron content was calculated per gram of crude tissue. Thedependence of boron content in tissues (μg.g⁻¹) was calculated from theaverage of 4-6 animals not indicating verified interval.

4. Biodistribution Results

The results of the biodistribution study of Na₂ [B₁₂ H₁₁ (SCN)] arepresented in Tables 1 and 2. The highest boron concentration in thetumour was found 1 hour after injection (48.9 μg/g), although at thistime, the skin content was similar (55.0 μg/g). The boron content in theblood 1 hour after injection was 2.5 times that in the tumour. Theoptimal ratio of boron in tumour to that in adjacent tissues wasachieved at 24 hours when the boron content of the tumour was 19.9 μg/gand the boron content of skin, muscles and blood were 1.7, 5.5 and 3.4times less than that in the tumour respectively.

The compound rapidly eliminated by the liver, kidneys and lung. Theelimination curves did not show renal intoxication.

The toxicological and pharmacokinetic characteristics suggest that Na₂[B₁₂ H₁₁ (SCN)] is a good candidate for the treatment of tumours byBNCT.

                  TABLE 1                                                         ______________________________________                                        Boron Content of Na.sub.2 [B.sub.12 H.sub.11 (SCN)] in Tissue (μg          · g.sup.-1)                                                                  Time after Administration of Compound                                         1 hour                                                                              2 hours   6 hours 24 hours                                      ______________________________________                                        Blood     120.7   10.4      8.7   5.8                                         Tumour    48.9    32.0      23.0  19.9                                        Skin      55.0    12.7      38.8  11.7                                        Muscle    10.4    7.6       12.9  3.6                                         Liver     216.0   38.1      37.9  9.8                                         Kidneys   123.3   27.1      10.5  5.2                                         Lung      115.8   19.5      11.8  4.5                                         Heart     49.6    16.1      9.5   9.9                                         ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Ratio of Boron in Tumour to Boron in Tissue for Na.sub.2 [B.sub.12            H.sub.11 (SCN)]                                                                       Time after Administration of Compound                                         1 hour                                                                              2 hours   6 hours 24 hours                                      ______________________________________                                        Blood     0.41    3.08      2.64  3.40                                        Skin      0.89    2.52      0.59  1.70                                        Muscle    4.70    4.23      1.78  5.50                                        Liver     0.23    0.84      0.61  2.02                                        Kidneys   0.40    1.18      2.19  3.84                                        Lung      0.42    1.64      1.95  4.41                                        Heart     0.99    1.98      2.42  2.01                                        ______________________________________                                    

What is claimed is:
 1. A process for the preparation ofundecahydrododecaborate anions [B₁₂ H.sub.(12-n) (XCN)_(n) ]²⁻ or [B₁₂H₁₁ XH]²⁻ or nonahydrodecaborate anions [B₁₀ H.sub.(10-n) (XCN)_(n) ]²⁻or [B₁₀ H₉ XH]²⁻ where X=O, S or Se; and n=1, 2 or 3; said processcomprising reacting, under chemical oxidizing conditions, adodecahydrododecaborate anion [B₁₂ H₁₂ ]²⁻ or decahydro decaborate anion[B₁₀ H₁₀ ]²⁻ with a compound A⁺ NCX⁻ where A⁺ =an alkali metal cationselected from Li⁺, Na⁺, K⁺ or Cs⁺ ; an alkaline earth metal cationselected from 1/2Ca⁺, 1/2Mg⁺ ; [R₄ P]⁺, [R₃ HP]⁺, [R₄ N]⁺, [R₃ HN]⁺ ;where R is a C₁₋₂₀ alkyl, aryl, or C₁₋₂₀ alkyl substituted aryl group.2. The process according to claim 1 wherein the reaction is conducted inthe presence of a chemical oxidizing agent selected from hydrogenperoxide, benzoyl peroxide, cupric ion, ceric ion, chromate ion,dichromate ion or halogen.
 3. The process according to claim 1 whereinthe [B₁₂ H₁₂ ]²⁻ anion starting material is selected from [R₄ N]₂ [B₁₂H₁₂ ], [R₃ NH]₂ [B₁₂ H₁₂ ], or (W)₂ [B₁₂ H₁₂ ] wherein R is selectedfrom methyl, ethyl, propyl or butyl and W represents Cs⁺, K⁺, Na⁺ orLi⁺.
 4. The process according to claim 1 wherein A⁺ is selected fromalkali metal cations selected from Li⁺, Na⁺, K⁺ or Cs⁺ ; alkaline earthmetal cations selected from 1/2 Ca⁺ and 1/2 Mg⁺ ; and [R₄ P]⁺, [R₃ HP]⁺,[R₄ N]⁺ or [R₃ HN]⁺ where R is selected from C₁ -C₂₀ alkyl, aryl or C₁-C₂₀ alkyl substituted aryl group.
 5. The process according to claim 1wherein R is selected from C₁ -C₈ alkyl, phenyl, tolyl and naphthyl. 6.The process according to claim 1 wherein the [B₁₂ H₁₂ ]²⁻ anion is inthe form [(C₂ H₅)₃ NH]₂ [B₁₂ H₁₂ ].